Regulatory Mechanisms Controlling TFH Responses in Lupus

摘要 尽管我们在理解导致这些疾病的致病机制方面取得了重大进展， 系统性红斑狼疮（SLE）的发展许多SLE患者继续生活在恶劣的环境中， 控制疾病。我们开发SLE新疗法的一个主要障碍是 这种疾病伴随着异质性，这部分是由于辅助性T细胞和调节性T细胞的复杂性， 细胞亚群在TH亚群中，TFH细胞在狼疮发病机制中起主要作用，这是由于它们在免疫调节中的关键作用。 驱动体液反应。TFH细胞的发育需要Bcl 6，Bcl 6的过表达足以驱动TFH细胞的生长。 TFH分化表明Bcl 6表达的严格控制对于确保TFH的适当调节是必要的 细胞数量。使用缺乏DEF 6和SWAP-70的小鼠（DKO小鼠）， 调节剂的缺乏导致狼疮的自发发展，我们最近发现了一个新的 Bcl 6的表达和TFH细胞的扩增的调控机制。事实上，DKO小鼠表现出 由于Bcl 6的异常翻译导致TFH细胞的积累。DKO TH细胞中Bcl 6翻译的增加是DKO TH细胞中Bcl 6翻译增加的原因。 增强的mTORC 1活化继发于调节细胞组装的途径的异常控制的结果， raptor-p62-TRAF 6复合物。蛋白质组学方法表明，DKO TH中Bcl 6翻译的增强 细胞中的蛋白质表达异常伴随着选定数量的蛋白质的表达异常。除了细胞内 TFH细胞异常，TFH细胞及其特化效应细胞协调发育的不平衡 Treg亚群，滤泡调节性T（TFR）细胞，也可以促进自身免疫。Treg的分析 DKO小鼠中的一个群体揭示了TFR细胞的缺陷性扩增，但非TFR细胞的稳健积累 效应器T在这个提议中，我们将探讨一个假设，即TFH细胞的异常能力， 翻译机制与TFR细胞亚群中的缺陷结合可导致系统性自身免疫。我们将 还研究了相关的假设，即虽然TFR细胞中的缺陷可以促进异常自身抗体的产生， 非TFR效应调节性T细胞的同时扩增可以帮助限制这些调节性T细胞引起的组织损伤 autoAbs.具体来说，我们将：1）描述mTORC 1依赖性翻译的调控和作用， 在TFH细胞中编程，和2）剖析控制狼疮中效应Treg亚群的途径。而 SLE中的转录异常已被广泛研究，异常翻译的影响， 狼疮T细胞功能的机制很少受到关注。这些研究将提供关键的 新研究领域的信息，并可能发现新的治疗干预靶点。一 更好地了解狼疮中不同Treg亚群的参与， 深入了解这种疾病伴随的异质性，以及这一代人的重要信息， 的功能性T细胞的离体，这可能是最适合于特异性靶向SLE。

ABSTRACT Despite significant advances in our understanding of the pathogenic mechanisms responsible for the development of Systemic Lupus Erythematosus (SLE) many patients with SLE continue to live with poorly controlled disease. A major roadblock in our ability to develop novel treatments for SLE is the significant heterogeneity that accompanies this disorder, which is partly due to the complexity of T helper and regulatory T cell subsets. Amongst TH subsets, TFH cells play a major role in lupus pathogenesis due to their crucial role in driving humoral responses. TFH cell development requires Bcl6 and overexpression of Bcl6 is sufficient to drive TFH differentiation indicating that tight control of Bcl6 expression is essential to ensure proper regulation of TFH cell numbers. Using mice lacking DEF6 and SWAP-70 (DKO mice), two members of a unique family of immune regulators whose absence leads to the spontaneous development of lupus, we have recently uncovered a new mechanism controlling the expression of Bcl6 and the expansion of TFH cells. Indeed DKO mice exhibit an accumulation of TFH cells due to aberrant translation of Bcl6. Increased translation of Bcl6 in DKO TH cells is the result of enhanced mTORC1 activation secondary to aberrant control of a pathway regulating the assembly of a raptor-p62-TRAF6 complex. A proteomic approach demonstrated that enhanced Bcl6 translation in DKO TH cells is accompanied by dysregulated expression of a selected number of proteins. In addition to cell-intrinsic abnormalities in TFH cells, imbalances in the coordinated development of TFH cells and its specialized effector Treg subset, follicular regulatory T (TFR) cells, can also promote autoimmunity. An analysis of the Treg population in DKO mice has revealed a defective expansion of TFR cells but a robust accumulation of non-TFR effector Tregs. In this proposal we will explore the hypothesis that an aberrant ability of TFH cells to employ translational mechanisms coupled with defects in the TFR cell subset can lead to systemic autoimmunity. We will also investigate the related hypothesis that while defects in TFR cells can fuel aberrant autoantibody production, the simultaneous expansion of non-TFR effector Tregs can help limit the tissue damage promoted by these autoAbs. Specifically we will: 1) Delineate the regulation and role of mTORC1-dependent translational programming in TFH cells, and 2) Dissect the pathways controlling effector Treg subsets in lupus. While transcriptional abnormalities in SLE have been extensively investigated, the impact of aberrant translational mechanisms on the function of lupus T cells has received little attention. These studies will thus provide critical information on a new area of investigation and potentially uncover novel targets for therapeutic intervention. A better understanding of the involvement of different Treg subsets in lupus could furthermore provide new insights into the heterogeneity that accompanies this disease as well as important information for the generation of functional Tregs ex vivo, which could be optimally suited to specifically target SLE.